Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficie...Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficient in situ tumor vaccine called Vac-SM,utilizing shikonin(SKN)to induce immunogenic cell death(ICD)and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy.SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators,respectively.Compared with the control group,the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis,while also improving survival rates.Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells(DCs),and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment,based on flow cytometry analysis results.Collectively,the Vac-SM vaccine effectively induces ICD,improves antigen presentation by DCs,activates a specific systemic antitumor T-cell immune response,exhibits a favorable safety profile,and holds the promise for clinical translation for local tumor immunotherapy.展开更多
背景与目的免疫治疗的应用大大改善了肺癌患者的临床结局。很大一部分肺癌患者能从程序性死亡受体1(programmed cell death 1,PD-1)/程序性死亡配体1(programmed cell death ligand 1,PD-L1)单抗治疗中获益,然而,仍有一部分耐药患者疗...背景与目的免疫治疗的应用大大改善了肺癌患者的临床结局。很大一部分肺癌患者能从程序性死亡受体1(programmed cell death 1,PD-1)/程序性死亡配体1(programmed cell death ligand 1,PD-L1)单抗治疗中获益,然而,仍有一部分耐药患者疗效不佳,临床上迫切需要能早期、便捷识别获益人群的生物标志物。在此,本研究回顾性分析了PD-1抗体治疗对局部晚期无法手术或转移性肺癌患者的疗效,并初步探索了外周血免疫指标与患者临床反应的相关性。方法该单中心研究共纳入2020年3月至2021年12月接受PD-1/PD-L1抗体治疗的ⅢA-Ⅳ期肺癌患者61例,收集PD-1/PD-L1抗体一线或后线治疗的病历数据。检测并分析患者外周血血清中多重Th1和Th2细胞因子水平以及外周血T细胞表型,探索细胞因子水平、T细胞表型等和患者临床反应之间的关系。结果入组患者均完成至少2个周期PD-1/PD-L1单抗治疗。其中,42例(68.9%)患者获得部分缓解(partial response,PR),7例(11.5%)患者疾病稳定(stable disease,SD),12例(19.7%)患者疾病进展(progressive disease,PD)。治疗前,疾病控制(disease control rate,DCR)组(有效组)患者外周血干扰素γ(interferon gamma,IFN-γ)(P=0.023)、肿瘤坏死因子α(tumor necrosis factorα,TNF-α)(P=0.007)和白介素5(interleukin 5,IL-5)(P=0.002)水平高于PD组(无效组)患者。此外,PD-1/PD-L1抗体治疗后外周血淋巴细胞绝对计数的减少与疾病进展有关联(P=0.023)。治疗后血清中IL-5(P=0.0027)和IL-10(P=0.0208)水平较治疗前明显升高。结论肺癌患者外周血血清IFN-γ、TNF-α和IL-5水平在预测抗PD-1阻断治疗临床疗效方面有一定的作用,肺癌患者外周血淋巴细胞绝对计数的减少与疾病进展有一定相关性,还需要大型前瞻性研究进一步阐明这些生物标志物的价值。展开更多
Objective： To study the method of cryopreserving rat hepatocytes and double collagen gel culture measurement after its cryopreservation. Methods： Rat hepatocytes, isolated by two-step perfusion with collagenase usin...Objective： To study the method of cryopreserving rat hepatocytes and double collagen gel culture measurement after its cryopreservation. Methods： Rat hepatocytes, isolated by two-step perfusion with collagenase using an extra corporeal perfusion apparatus, were cryopreserved in double collagen gel with culture medium added by epidermal growth factor（EGF）. The expression of cell function and cellular morphology were examined during culture. Results： The hepatocytes cryopreserved in double collagen gel concluding EGF showed good morphology and biological characteristics. After thawing, the MTT metabolism and protein synthesis of hepatocytes in sandwich ± EGF groups were better than those in control group. And the morphology and function of hepatocytes in sandwich group was better than that in EGF group（P 〈 0.05）. Conclusion： Double collagen gel culture can keep hepatocyte＇s activities. Thawed hepatocytes can be cultivated with collagenous matrix, which provides an environment that more closely resembles that in vivo and maintain the expression of certain liver-specific function of hepatocytes.展开更多
MDM2 (the product of murine double minute 2 gene) is one of the most important negative regulators of p53,which can binds to p53 and initiates ubiquitin-mediated degradation.Besides,MDM2 also controls the activity of ...MDM2 (the product of murine double minute 2 gene) is one of the most important negative regulators of p53,which can binds to p53 and initiates ubiquitin-mediated degradation.Besides,MDM2 also controls the activity of several cell-cycle regulators,e.g.pRB,p21,E2F1,independently of p53.The important role of MDM2 in cell-cycle regulation indicates it to be a point of interest in cancer research.In recent years,studies revealed that MDM2 participated in the genesis and development of human tumors.The expression levels and activity of MDM2 was associated with the invasion,metastasis,prognosis and more practical,chemosensitivity.MDM2 is becoming a novel biomarker in cancer prognosis and chemosensitivity prediction.展开更多
Peripheral T-cell lymphoma, not otherwise specified （PTCL-NOS） is a heterogeneous group of aggressive T-ce lymphomas with no treatment consensus and poor prognosis. We herein described an extraordinary refractory ca...Peripheral T-cell lymphoma, not otherwise specified （PTCL-NOS） is a heterogeneous group of aggressive T-ce lymphomas with no treatment consensus and poor prognosis. We herein described an extraordinary refractory case of PTCL-NOS with widely involvement of subcutaneous tissue, which showed an excellent response to Semustine personal- ized chemotherapy based on the detection finding of positive O6-methylguanine-DNA methyltransferase （MGMT） promoter methylation. This is the first english report to indicate that single nitrosourea agent such as Semustine may have good efficacy and safety for widespread subcutaneous involvement of PTCL-NOS with positive MGMT promoter methylation.展开更多
Engineered bacteria have shown great potential in cancer immunotherapy by dynamically releasing therapeutic payloads and inducing sustained antitumor immune response with the crosstalk of immune cells.In previous stud...Engineered bacteria have shown great potential in cancer immunotherapy by dynamically releasing therapeutic payloads and inducing sustained antitumor immune response with the crosstalk of immune cells.In previous studies,FOLactis was designed,which could secret an encoded fusion protein of Fms-related tyrosine kinase 3 ligand and co-stimulator OX40 ligand,leading to remarkable tumor suppression and exerting an abscopal effect by intratumoral injection.However,it is difficult for intratumoral administration of FOLactis in solid tumors with firm texture or high internal pressure.For patients without lesions such as abdominal metastatic tumors and orthotopic gastric tumors,intratumoral injection is not feasible and peritumoral maybe a better choice.Herein,an engineered bacteria delivery system is constructed based on in situ temperature-sensitive poloxamer 407 hydrogels.Peritumoral injection of FOLactis/P407 results in a 5-fold increase in the proportion of activated DC cells and a more than 2-fold increase in the proportion of effective memory T cells(TEM),playing the role of artificial lymph island.Besides,administration of FOLactis/P407 significantly inhibits the growth of abdominal metastatic tumors and orthotopic gastric tumors,resulting in an extended survival time.Therefore,these findings demonstrate the delivery approach of engineered bacteria based on in situ hydrogel will promote the efficacy and universality of therapeutics.展开更多
Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-pa...Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine(PAAG)in patients with first-line mPC(NCT05493995).The primary endpoints included the objective response rate(ORR)and disease control rate(DCR),while secondary endpoints encompassed progression-free survival(PFS),overall survival(OS),and safety.In 66 patients analysed for efficacy,the best response,indicated by the ORR,was recorded at 50.0%(33/66)(95%CI,37.4–62.6%),with 33 patients achieving partial response(PR).Notably,the DCR was 95.5%(63/66,95%CI,87.3–99.1%).The median PFS(mPFS)and OS(mOS)were 8.8(95%CI,8.1–11.6),and 13.7(95%CI,12.4 to not reached)months,respectively.Grade 3/4 treatment-related adverse events(TRAEs)were reported in 39.4%of patients(26/66).In prespecified exploratory analysis,patients with altered SWI/SNF complex had a poorer PFS.Additionally,low serum CA724 level,high T-cell recruitment,low Th17 cell recruitment,and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy.In conclusion,PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC.The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.展开更多
Background:Hepatocellular carcinoma(HCC)persists as a dominant cause of cancer-related mortality globally,with a notably rapid escalation in mortality rates.The advent of immunotherapy,particularly immune checkpoint i...Background:Hepatocellular carcinoma(HCC)persists as a dominant cause of cancer-related mortality globally,with a notably rapid escalation in mortality rates.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has ushered in a new era in the management of liver cancer,albeit with unresolved challenges in the context of treatment beyond progression(TBP)and stratified prognosis in diverse populations.This study aimed to develop and validate a novel nomogram model to identify factors that predict the benefit of continued immunotherapy for hepatocellular carcinoma patients following disease progression in clinical practice.Methods:This study retrospectively analyzed the efficacy of ICIs in TBP,focusing on the Chinese population with advanced liver cancer.A nomogram was constructed based on four independent risk factors identified through Cox multivariate analysis,aiming to predict patient prognosis post-ICI treatment.The model was validated through receiver operating characteristic(ROC)curve analysis and categorized patients into high-,intermediate-,and low-risk groups,with further validation using calibration plots and decision curve analysis(DCA).Results:The low-risk group demonstrated significantly enhanced overall survival(OS)compared to the high-risk group,with the nomogram predictions aligning closely with actual outcomes for 6-and 9-month OS.The model exhibited commendable predictive accuracy,achieving a C-index exceeding 0.7 in both training and validation datasets.The DCA underscored the clinical utility of the nomogram-based prognostic model,further substantiated by the area under the ROC curve(AUC).Conclusions:The developed nomogram presents a potentially valuable tool for predicting the prognosis of HCC patients undergoing ICI therapy beyond progression,particularly within the Chinese demographic.However,the study is constrained by its retrospective,single-center nature and necessitates further validation through large-scale,multicenter clinical studies across varied populations.展开更多
The technical bottleneck of carbon materials as counter electrodes(CEs)lies in their limited electrical conduc-tivity,extended ion diffusion paths,poor dispersion,and high contact resistance.Problem-oriented in-situ s...The technical bottleneck of carbon materials as counter electrodes(CEs)lies in their limited electrical conduc-tivity,extended ion diffusion paths,poor dispersion,and high contact resistance.Problem-oriented in-situ self-grown N-doped CNTs-coated Ni nanoparticles based on N-doped carbonaceous structures derived from pitaya peel(PC)are adopted to construct Ni-N-C hybrid 3D ionized network sites(Ni@NCNTs/PC-4)as CEs.Structural characterization,micromorphological and chemical composition analyses revealed the 3D network structure of Ni@NCNTs/PC-4 with abundant active sites.They effectively shorten the diffusion distance of I 3−ions with a smaller charge transfer resistance(5.21Ω)than that of PC(12.53Ω).DSSCs based on Ni@NCNTs/PC-4 display good optoelectronic properties,in which the short-circuit current density(Jsc)is 13.27 mA/cm^(2),higher than those of Pt(11.66 mA/cm^(2))and PC(6.99 mA/cm^(2)).The PCE value(5.13%)of DSSCs based on Ni@NCNTs/PC-4 is also higher than that of DSSCs based on PC(2.47%).Overall,this work provides a preliminary research and new ideas for further in-depth study of biomass-derived 3D structured-carbons that contribute to key electrodes in DSSCs.展开更多
基金supported by grants from the Natural Science Foundation of Huai'an Science and Technology Bureau(Grant No.HAB202312)the Science and Technology Development Fund of the Affiliated Hospital of Xuzhou Medical University(Grant No.XYFY2021018).
文摘Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficient in situ tumor vaccine called Vac-SM,utilizing shikonin(SKN)to induce immunogenic cell death(ICD)and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy.SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators,respectively.Compared with the control group,the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis,while also improving survival rates.Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells(DCs),and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment,based on flow cytometry analysis results.Collectively,the Vac-SM vaccine effectively induces ICD,improves antigen presentation by DCs,activates a specific systemic antitumor T-cell immune response,exhibits a favorable safety profile,and holds the promise for clinical translation for local tumor immunotherapy.
文摘Objective： To study the method of cryopreserving rat hepatocytes and double collagen gel culture measurement after its cryopreservation. Methods： Rat hepatocytes, isolated by two-step perfusion with collagenase using an extra corporeal perfusion apparatus, were cryopreserved in double collagen gel with culture medium added by epidermal growth factor（EGF）. The expression of cell function and cellular morphology were examined during culture. Results： The hepatocytes cryopreserved in double collagen gel concluding EGF showed good morphology and biological characteristics. After thawing, the MTT metabolism and protein synthesis of hepatocytes in sandwich ± EGF groups were better than those in control group. And the morphology and function of hepatocytes in sandwich group was better than that in EGF group（P 〈 0.05）. Conclusion： Double collagen gel culture can keep hepatocyte＇s activities. Thawed hepatocytes can be cultivated with collagenous matrix, which provides an environment that more closely resembles that in vivo and maintain the expression of certain liver-specific function of hepatocytes.
基金Supported by a grant from the National Natural Sciences Foundation of China (No.200803150007)
文摘MDM2 (the product of murine double minute 2 gene) is one of the most important negative regulators of p53,which can binds to p53 and initiates ubiquitin-mediated degradation.Besides,MDM2 also controls the activity of several cell-cycle regulators,e.g.pRB,p21,E2F1,independently of p53.The important role of MDM2 in cell-cycle regulation indicates it to be a point of interest in cancer research.In recent years,studies revealed that MDM2 participated in the genesis and development of human tumors.The expression levels and activity of MDM2 was associated with the invasion,metastasis,prognosis and more practical,chemosensitivity.MDM2 is becoming a novel biomarker in cancer prognosis and chemosensitivity prediction.
文摘Peripheral T-cell lymphoma, not otherwise specified （PTCL-NOS） is a heterogeneous group of aggressive T-ce lymphomas with no treatment consensus and poor prognosis. We herein described an extraordinary refractory case of PTCL-NOS with widely involvement of subcutaneous tissue, which showed an excellent response to Semustine personal- ized chemotherapy based on the detection finding of positive O6-methylguanine-DNA methyltransferase （MGMT） promoter methylation. This is the first english report to indicate that single nitrosourea agent such as Semustine may have good efficacy and safety for widespread subcutaneous involvement of PTCL-NOS with positive MGMT promoter methylation.
基金supported by the National Natural Science Foundation of China (82272811 and 81930080)the Fund for Distinguished Young Scholars of Jiangsu Province (BK20230001).
文摘Engineered bacteria have shown great potential in cancer immunotherapy by dynamically releasing therapeutic payloads and inducing sustained antitumor immune response with the crosstalk of immune cells.In previous studies,FOLactis was designed,which could secret an encoded fusion protein of Fms-related tyrosine kinase 3 ligand and co-stimulator OX40 ligand,leading to remarkable tumor suppression and exerting an abscopal effect by intratumoral injection.However,it is difficult for intratumoral administration of FOLactis in solid tumors with firm texture or high internal pressure.For patients without lesions such as abdominal metastatic tumors and orthotopic gastric tumors,intratumoral injection is not feasible and peritumoral maybe a better choice.Herein,an engineered bacteria delivery system is constructed based on in situ temperature-sensitive poloxamer 407 hydrogels.Peritumoral injection of FOLactis/P407 results in a 5-fold increase in the proportion of activated DC cells and a more than 2-fold increase in the proportion of effective memory T cells(TEM),playing the role of artificial lymph island.Besides,administration of FOLactis/P407 significantly inhibits the growth of abdominal metastatic tumors and orthotopic gastric tumors,resulting in an extended survival time.Therefore,these findings demonstrate the delivery approach of engineered bacteria based on in situ hydrogel will promote the efficacy and universality of therapeutics.
基金National Key Research and Development Program of China(2020YFA0713804)the National Natural Science Foundation of China(82272811)+2 种基金Jiangsu Province Key Research and Development Program(BE2023654)Nanjing Jiangbei New Area Key Research and Development Program,Special Fund of Health Science and Technology Development of Nanjing(YKK20080)Fundings for Clinical Trials from the Affiliated Drum Tower Hospital,Medical School of Nanjing University(2023-LCYJ-PY-29).
文摘Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine(PAAG)in patients with first-line mPC(NCT05493995).The primary endpoints included the objective response rate(ORR)and disease control rate(DCR),while secondary endpoints encompassed progression-free survival(PFS),overall survival(OS),and safety.In 66 patients analysed for efficacy,the best response,indicated by the ORR,was recorded at 50.0%(33/66)(95%CI,37.4–62.6%),with 33 patients achieving partial response(PR).Notably,the DCR was 95.5%(63/66,95%CI,87.3–99.1%).The median PFS(mPFS)and OS(mOS)were 8.8(95%CI,8.1–11.6),and 13.7(95%CI,12.4 to not reached)months,respectively.Grade 3/4 treatment-related adverse events(TRAEs)were reported in 39.4%of patients(26/66).In prespecified exploratory analysis,patients with altered SWI/SNF complex had a poorer PFS.Additionally,low serum CA724 level,high T-cell recruitment,low Th17 cell recruitment,and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy.In conclusion,PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC.The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.
基金supported by the Jiangsu Provincial Graduate Student Practice Innovation Project(No.JX22013930)the Internal Research Fund Project of Jinling Hospital Affiliated to Nanjing Medical University(No.22LCZLXJS21)the Internal Research Fund Project of Jinling Hospital Affiliated to Nanjing Medical University(No.22LCYY-LH5).
文摘Background:Hepatocellular carcinoma(HCC)persists as a dominant cause of cancer-related mortality globally,with a notably rapid escalation in mortality rates.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has ushered in a new era in the management of liver cancer,albeit with unresolved challenges in the context of treatment beyond progression(TBP)and stratified prognosis in diverse populations.This study aimed to develop and validate a novel nomogram model to identify factors that predict the benefit of continued immunotherapy for hepatocellular carcinoma patients following disease progression in clinical practice.Methods:This study retrospectively analyzed the efficacy of ICIs in TBP,focusing on the Chinese population with advanced liver cancer.A nomogram was constructed based on four independent risk factors identified through Cox multivariate analysis,aiming to predict patient prognosis post-ICI treatment.The model was validated through receiver operating characteristic(ROC)curve analysis and categorized patients into high-,intermediate-,and low-risk groups,with further validation using calibration plots and decision curve analysis(DCA).Results:The low-risk group demonstrated significantly enhanced overall survival(OS)compared to the high-risk group,with the nomogram predictions aligning closely with actual outcomes for 6-and 9-month OS.The model exhibited commendable predictive accuracy,achieving a C-index exceeding 0.7 in both training and validation datasets.The DCA underscored the clinical utility of the nomogram-based prognostic model,further substantiated by the area under the ROC curve(AUC).Conclusions:The developed nomogram presents a potentially valuable tool for predicting the prognosis of HCC patients undergoing ICI therapy beyond progression,particularly within the Chinese demographic.However,the study is constrained by its retrospective,single-center nature and necessitates further validation through large-scale,multicenter clinical studies across varied populations.
基金supported by the National Natural Science Foundation of China(31960293).
文摘The technical bottleneck of carbon materials as counter electrodes(CEs)lies in their limited electrical conduc-tivity,extended ion diffusion paths,poor dispersion,and high contact resistance.Problem-oriented in-situ self-grown N-doped CNTs-coated Ni nanoparticles based on N-doped carbonaceous structures derived from pitaya peel(PC)are adopted to construct Ni-N-C hybrid 3D ionized network sites(Ni@NCNTs/PC-4)as CEs.Structural characterization,micromorphological and chemical composition analyses revealed the 3D network structure of Ni@NCNTs/PC-4 with abundant active sites.They effectively shorten the diffusion distance of I 3−ions with a smaller charge transfer resistance(5.21Ω)than that of PC(12.53Ω).DSSCs based on Ni@NCNTs/PC-4 display good optoelectronic properties,in which the short-circuit current density(Jsc)is 13.27 mA/cm^(2),higher than those of Pt(11.66 mA/cm^(2))and PC(6.99 mA/cm^(2)).The PCE value(5.13%)of DSSCs based on Ni@NCNTs/PC-4 is also higher than that of DSSCs based on PC(2.47%).Overall,this work provides a preliminary research and new ideas for further in-depth study of biomass-derived 3D structured-carbons that contribute to key electrodes in DSSCs.
